scholarly journals Alteration of the natural killer repertoire in H-2 transgenic mice: specificity of rapid lymphoma cell clearance determined by the H-2 phenotype of the target.

1991 ◽  
Vol 174 (2) ◽  
pp. 327-334 ◽  
Author(s):  
P Höglund ◽  
R Glas ◽  
C Ohlén ◽  
H G Ljunggren ◽  
K Kärre
Keyword(s):  
Natural Killer ◽  
Nk Cell ◽  
Class I ◽  
Tumor Resistance ◽  
Lymphoma Cells ◽  
Cell Clearance ◽  
Differential Elimination ◽  
Missing Self ◽  
I Gene

The mechanism behind natural tumor resistance conveyed by a H-2Dd transgene to C57Bl/6 (B6) mice was investigated. Transgenic D8 mice were more efficient than control mice in natural killer (NK) cell mediated rapid elimination of intravenously inoculated radiolabeled lymphoma cells of B6 origin, such as RBL-5. There was no difference between D8 and B6 mice when elimination of YAC-1 targets was monitored. The effect of the transgene on the NK repertoire was related to the H-2 phenotype of the target: the differential elimination of RBL-5 lymphoma cells in D8 and B6 mice was not seen when a H-2 deficient variant of this line was used (efficiently eliminated in both genotypes), nor was it seen with a H-2Dd transfectant (surviving in both genotypes). The data show that a MHC class I transgene can directly control natural killing in vivo by altering the repertoire rather than the general levels of NK activity. Since the NK mediated elimination seen after introduction of a novel gene in the host was neutralized by introducing the same gene (H-2Dd), but not an unrelated class I gene (H-2Dp), in the tumor, the data support the concept of NK surveillance against missing self. This combined transgenic/transfectant system may serve as a tool for a molecular dissection of the interactions between NK cells and their targets in vivo.

scholarly journals Inducible down-regulation of MHC class I results in natural killer cell tolerance

2018 ◽  
Vol 216 (1) ◽  
pp. 99-116 ◽  
Author(s):  
Michael D. Bern ◽  
Bijal A. Parikh ◽  
Liping Yang ◽  
Diana L. Beckman ◽  
Jennifer Poursine-Laurent ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Cell Tolerance ◽  
Down Regulation ◽  
Mhc I ◽  
Missing Self

Natural killer (NK) cells are innate lymphocytes that are thought to kill cells that down-regulate MHC class I (MHC-I) through “missing-self” recognition. NK cells from B2m−/− mice that lack surface MHC-I, however, are not autoreactive as predicted by the missing-self hypothesis. As a result, it is unclear if MHC-I down-regulation in vivo induces NK cell reactivity or tolerance to missing-self. Here, we generated a floxed B2m mouse to acutely down-regulate MHC-I in vivo in a host that normally expresses MHC-I. Global down-regulation of MHC-I induced NK cell hyporesponsiveness and tolerance to missing-self without overt missing-self reactivity. In contrast, down-regulation of MHC-I on a small fraction of hematopoietic cells triggered missing-self reactivity. Surprisingly, down-regulation of MHC-I only on CD4+ T cells predominately induced tolerance to missing-self without resetting NK cell responsiveness. In this setting, inflammation triggered substantial missing-self reactivity. These results show that MHC-I down-regulation can induce either NK cell tolerance or killing in vivo and that inflammation promotes missing-self reactivity.

scholarly journals Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies

Blood ◽  
2014 ◽  
Vol 123 (5) ◽  
pp. 678-686 ◽  
Author(s):  
Holbrook E. Kohrt ◽  
Ariane Thielens ◽  
Aurelien Marabelle ◽  
Idit Sagiv-Barfi ◽  
Caroline Sola ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Lymphoma Cells ◽  
Killer Cells ◽  
Key Points ◽  
Anti Cd20 ◽  
Cd20 Antibodies

Key Points Blockade of inhibitory KIRs with MHC class I antigens on lymphoma cells by anti-KIR antibodies augments NK-cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR induces enhanced NK cell–mediated, rituximab-dependent cytotoxicity against lymphoma.

scholarly journals HLA upregulation during dengue virus infection suppresses the natural killer cell response

2019 ◽  
Author(s):  
Julia L. McKechnie ◽  
Davis Beltran ◽  
Arcelys Pitti ◽  
Lisseth Saenz ◽  
Ana B. Araúz ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Response ◽  
Nk Cell ◽  
Hla Class I ◽  
Denv Infection ◽  
Class I ◽  
Hla Class I Molecules

AbstractDengue virus (DENV) is the most prevalent mosquito-borne virus in the world and a major cause of morbidity in the tropics and subtropics. Upregulation of HLA class I molecules has long been considered a feature of DENV infection, yet this has not been evaluated in the setting of natural infection. Natural killer (NK) cells, an innate immune cell subset critical for mounting an early response to viral infection, are inhibited by self HLA class I, suggesting that upregulation of HLA class I during DENV infection could dampen the NK cell response. Here we addressed whether upregulation of HLA class I molecules occurs during in vivo DENV infection and, if so, whether this suppresses the NK cell response. We found that HLA class I expression was indeed upregulated during acute DENV infection across multiple cell lineages in vivo. To better understand the role of HLA class I upregulation, we infected primary human monocytes, a major target of DENV infection, in vitro. Upregulation of total HLA class I is dependent on active viral replication and is mediated in part by cytokines and other soluble factors induced by infection, while upregulation of HLA-E occurs in the presence of replication-incompetent virus. Importantly, blocking DENV-infected monocytes with a pan-HLA class I Fab nearly doubles the frequency of degranulating NK cells, while blocking HLA-E does not significantly improve the NK cell response. These findings demonstrate that upregulation of HLA class I during DENV infection suppresses the NK cell response, potentially contributing to disease pathogenesis.

scholarly journals M144, a Murine Cytomegalovirus (Mcmv)-Encoded Major Histocompatibility Complex Class I Homologue, Confers Tumor Resistance to Natural Killer Cell–Mediated Rejection

1999 ◽  
Vol 190 (3) ◽  
pp. 435-444 ◽  
Author(s):  
Erika Cretney ◽  
Mariapia A. Degli-Esposti ◽  
Eloise H. Densley ◽  
Helen E. Farrell ◽  
Nick J. Davis-Poynter ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Line ◽  
Nk Cell ◽  
Effector Function ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Cell Effector Function ◽  
Cell Effector

Until now, it has been unclear whether murine cytomegalovirus (MCMV)-encoded protein m144 directly regulates natural killer (NK) cell effector function and whether the effects of m144 are only strictly evident in the context of MCMV infection. We have generated clones of the transporter associated with antigen processing (TAP)-2–deficient RMA-S T lymphoma cell line and its parent cell line, RMA, that stably express significant and equivalent levels of m144. In vivo NK cell–mediated rejection of RMA-S-m144 lymphomas was reduced compared with rejection of parental or mock-transfected RMA-S clones, indicating the ability of m144 to regulate NK cell–mediated responses in vivo. Significantly, the accumulation of NK cells in the peritoneum was reduced in mice challenged with RMA-S-m144, as was the lytic activity of NK cells recovered from the peritoneum. Expression of m144 on RMA-S cells also conferred resistance to cytotoxicity mediated in vitro by interleukin 2–activated adherent spleen NK cells. In summary, the data demonstrate that m144 confers some protection from NK cell effector function mediated in the absence of target cell class I expression, but that in vivo the major effect of m144 is to regulate NK cell accumulation and activation at the site of immune challenge.

scholarly journals Natural Killer Cell Tolerance in Mice with Mosaic Expression of Major Histocompatibility Complex Class I Transgene

1997 ◽  
Vol 186 (3) ◽  
pp. 353-364 ◽  
Author(s):  
Maria H. Johansson ◽  
Charles Bieberich ◽  
Gilbert Jay ◽  
Klas Kärre ◽  
Petter Höglund
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Cell Tolerance ◽  
Histocompatibility Complex ◽  
Missing Self

We have studied natural killer (NK) cell tolerance in a major histocompatibility complex (MHC) class I transgenic line, DL6, in which the transgene product was expressed on only a fraction of blood cells. In contrast with transgenic mice expressing the same transgene in all cells, NK cells from mosaic mice failed to reject transgene-negative bone marrow or lymphoma grafts. However, they retained the capability to reject cells with a total missing-self phenotype, i.e., cells lacking also wild-type MHC class I molecules. Tolerance against transgene-negative cells was demonstrated also in vitro, and could be broken if transgene-positive spleen cells of mosaic mice were separated from negative cells before, or after 4 d of culture in interleukin-2. The results provide support for selective NK cell tolerance to one particular missing-self phenotype but not to another. We suggest that this tolerance is determined by NK cell interactions with multiple cells in the environment, and that it is dominantly controlled by the presence of cells lacking a specific MHC class I ligand. Furthermore, the tolerant NK cells could be reactivated in vitro, which suggests that the tolerance occurs without deletion of the potentially autoreactive NK cell subset(s), and that it may be dependent upon the continuous presence of tolerizing cells.

scholarly journals Recruitment and Activation of Natural Killer (Nk) Cells in Vivo Determined by the Target Cell Phenotype

2000 ◽  
Vol 191 (1) ◽  
pp. 129-138 ◽  
Author(s):  
Rickard Glas ◽  
Lars Franksson ◽  
Clas Une ◽  
Maija-Leena Eloranta ◽  
Claes Öhlén ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Interferon Γ ◽  
Class I ◽  
Cell Phenotype ◽  
Target Cells

Natural killer (NK) cells can spontaneously lyse certain virally infected and transformed cells. However, early in immune responses NK cells are further activated and recruited to tissue sites where they perform effector functions. This process is dependent on cytokines, but it is unclear if it is regulated by NK cell recognition of susceptible target cells. We show here that infiltration of activated NK cells into the peritoneal cavity in response to tumor cells is controlled by the tumor major histocompatibility complex (MHC) class I phenotype. Tumor cells lacking appropriate MHC class I expression induced NK cell infiltration, cytotoxic activation, and induction of transcription of interferon γ in NK cells. The induction of these responses was inhibited by restoration of tumor cell MHC class I expression. The NK cells responding to MHC class I–deficient tumor cells were ∼10 times as active as endogenous NK cells on a per cell basis. Although these effector cells showed a typical NK specificity in that they preferentially killed MHC class I–deficient cells, this specificity was even more distinct during induction of the intraperitoneal response. Observations are discussed in relation to a possible adaptive component of the NK response, i.e., recruitment/activation in response to challenges that only NK cells are able to neutralize.

scholarly journals Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo

2010 ◽  
Vol 207 (12) ◽  
pp. 2663-2673 ◽  
Author(s):  
Marina Babić ◽  
Michal Pyzik ◽  
Biljana Zafirova ◽  
Maja Mitrović ◽  
Višnja Butorac ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Physiological Role ◽  
Dependent Manner ◽  
Class I Mhc ◽  
Mhc I ◽  
Missing Self

Cytomegaloviruses (CMVs) are renowned for interfering with the immune system of their hosts. To sidestep antigen presentation and destruction by CD8+ T cells, these viruses reduce expression of major histocompatibility complex class I (MHC I) molecules. However, this process sensitizes the virus-infected cells to natural killer (NK) cell–mediated killing via the “missing self” axis. Mouse cytomegalovirus (MCMV) uses m152 and m06 encoded proteins to inhibit surface expression of MHC I molecules. In addition, it encodes another protein, m04, which forms complexes with MHC I and escorts them to the cell surface. This mechanism is believed to prevent NK cell activation and killing by restoring the “self” signature and allowing the engagement of inhibitory Ly49 receptors on NK cells. Here we show that MCMV lacking m04 was attenuated in an NK cell– and MHC I–dependent manner. NK cell–mediated control of the infection was dependent on the presence of NK cell subsets expressing different inhibitory Ly49 receptors. In addition to providing evidence for immunoevasion strategies used by CMVs to avoid NK cell control via the missing-self pathway, our study is the first to demonstrate that missing self–dependent NK cell activation is biologically relevant in the protection against viral infection in vivo.

scholarly journals Coronaviruses induce the expression of the peptide antigen transporter TAP1.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Host Cell ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
The United States ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I

Coronavirus infection is an emerging public health threat in the United States and worldwide (1). We mined published microarray data to perform systems-level analysis of host cell transcription following infection with multiple coronavirus types in order to identify therapeutic targets and host cell vulnerabilities (2, 3). We identified the antigen peptide transported TAP1 as differentially expressed in vitro in a human cell line following infection with human coronavirus 229E and in vivo in the lungs of mice following infection with the severe acute respiratory distress syndrome SARS coronavirus. While TAP1 functions to enhance presentation of class I-associated peptides to CD8 cytotoxic T-cells, TAP1 also enhances presentation of major histocompatibility class I (MHC-I) receptors (4). One criteria natural killer cells use to lyse cells is the absence of surface MHC-I (5), and hepatitis C virus up-regulates TAP1 to increase surface expression of MHC-I and inhibit NK-cell cytotoxicity and promote infection (6). We propose coronaviruses similarly up-regulate TAP1 to impair natural killer cell-mediated cytotoxicity responses and avoid recognition by NK cells.

The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2434-2441 ◽  
Author(s):  
Petter Brodin ◽  
Tadepally Lakshmikanth ◽  
Sofia Johansson ◽  
Klas Kärre ◽  
Petter Höglund
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Interferon Γ ◽  
Class I ◽  
Inhibitory Input ◽  
Missing Self ◽  
Functional Responsiveness ◽  
Mhc Class I Molecules

Natural killer (NK) cells express inhibitory receptors for major histocompatibility complex (MHC) class I. If self-MHC is down-regulated or absent, lack of inhibition triggers “missing self” killing. NK cells developing in the absence of MHC class I are hypo-responsive, demonstrating that MHC class I molecules are required for NK-cell education. Here, we show that the number and the type of MHC class I alleles that are present during NK-cell education quantitatively determine the frequency of responding NK cells, the number of effector functions in individual NK cells, and the amount of interferon-γ production in NK cells of specific Ly49 subsets. A relationship between the extent of inhibitory signals during education and functional responsiveness was corroborated by an enhanced probability of NK cells expressing more than one inhibitory receptor for a single host self–MHC class I allele to degranulate after activation. Our data suggest that the capacity of an individual NK cell to respond to stimulation is quantitatively controlled by the extent of inhibitory signals that are received from MHC class I molecules during NK-cell education.

scholarly journals Acquisition of Ly49 Receptor Expression by Developing Natural Killer Cells

1998 ◽  
Vol 187 (4) ◽  
pp. 609-618 ◽  
Author(s):  
Jeffrey R. Dorfman ◽  
David H. Raulet
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Receptor Expression ◽  
Class I ◽  
Cell Repertoire ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
Histocompatibility Complex

The formation of the repertoire of mouse natural killer (NK) cell receptors for major histocompatibility complex (MHC) class I molecules was investigated by determining the developmental pattern of Ly49 receptor expression. During the first days after birth, few or no splenic NK cells express Ly49A, Ly49C, Ly49G2, or Ly49I receptors. The proportion of Ly49+ splenic NK cells gradually rises to adult levels during the first 6–8 wk of life. The appearance of appreciable numbers of splenic Ly49+ NK cells coincides with the appearance of NK activity at 3–4 wk. After in vivo transfer, NK cells not expressing specific Ly49 receptors can give rise to NK cells that do, and cells expressing one of these four Ly49 receptors can give rise to cells expressing others. Once initiated, expression of a Ly49 receptor is stable for at least 10 d after in vivo transfer. Hence, initiation of Ly49 receptor expression occurs successively. Interestingly, expression of one of the receptors tested, Ly49A, did not occur after in vivo transfer of Ly49A− cells. One possible explanation for these data is that the order of Ly49 receptor expression by NK cells is nonrandom. The results provide a framework for evaluating models of NK cell repertoire formation, and how the repertoire is molded by host class I MHC molecules.

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